1. A Diversity of Assembly Mechanisms of a Generic Amyloid Fold
Timo Eichner, Sheena E. Radford 
Molecular Cell 
Volume 43, Issue 1, Pages 8-18 (July 2011)
DOI: /j.molcel
Copyright © 2011 Elsevier Inc. Terms and Conditions

2. Figure 1
Hallmarks of Amyloid Exemplified by Fibrils Formed by Wild-Type β2m at pH 2.5, 37°C under 200 rpm Agitation
(A) X-ray fiber diffraction pattern showing reflections at 4.7 and ∼10 Å, consistent with a cross-β fibrillar architecture.
(B) Negative-stain EM images show the formation of classical long-straight fibrils (scale bar indicates 100 nm).
(C and D) Congo red staining as observed using a bright-field light microscope (C) and birefringence observed using a cross-polarized light microscope (D). (A)–(D) are taken from Jahn, 2006.
(E) Kinetics of spontaneous (de novo) fibril formation comprises two distinct stages: a lag phase corresponding to the formation of thermodynamically disfavored nucleation events and a rapid, thermodynamically favored elongation phase (black line). If preformed fibrils (seeds) are used as templates, the lag phase is radically shortened (red line). The image of the amyloid fibril shown is from White et al., 2009.
Molecular Cell  , 8-18DOI: ( /j.molcel )
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3. Figure 2
Diversity of Cross-β Structures Identified Using X-Ray Crystallography, ssNMR, or Cryo-EM
(A) Steric zipper conformation observed for the peptide MVGGVV derived from Aβ (residues 35–40) using microcrystallography (PDB 2ONA) (Sawaya et al., 2007).
(B) Crystal structure of wild-type β2m in a domain-swapped dimer conformation formed via intermolecular disulfide exchange (PDB 3LOW) (Liu et al., 2011).
(C) Crystal structure of protease inhibitor stefin B (cystatin B) in a domain-swapped dimer conformation (PDB 2OCT) implicated as an intermediate in amyloid formation (Jenko Kokalj et al., 2007).
(D) Structure of cross-β antiparallel in-register protein fibrils of the peptide NFGAIL derived from human amylin using ssNMR (PDB 2KIB) (Nielsen et al., 2009).
(E) Cross-β parallel in-register protein fibril of the K3 peptide of β2m (residues 20–41) determined using ssNMR (PDB 2E8D) (Iwata et al., 2006).
(F) Structural model of Aβ1-42 fibrils determined using hydrogen exchange, pairwise mutagenesis, and solution NMR (PDB 2BEG) (Lührs et al., 2005).
(G and H) High-resolution structural model of Aβ1-40 fibrils obtained under agitation or quiescent conditions, respectively, determined using ssNMR (Petkova et al., 2006; Paravastu et al., 2008).
(I) High-resolution structural model of Het-s( ) prion in its amyloid form obtained using ssNMR (PDB 2RNM) (Wasmer et al., 2008).
(J) Low-resolution three-dimensional structural model of amyloid fibrils assembled from full-length β2m based on a cryo-EM (White et al., 2009).
(K) Low-resolution three-dimensional structures of fibrils from the polypeptide hormone insulin containing 2, 4, or 6 protofilaments obtained by cryo-EM (Jiménez et al., 2002).
(L) Continuum of low-resolution three-dimensional fibrillar morphologies of Aβ1-40 revealed by cryo-EM (Meinhardt et al., 2009).
Molecular Cell  , 8-18DOI: ( /j.molcel )
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4. Figure 3 Folding and Aggregation Energy Landscapes
The folding energy landscape (shown in black) depicts folding intermediates on pathway to the native state and other partially folded conformers that are accessible to the polypeptide chain through thermal motions. In general, nonnative species are believed to be the structural link to the aggregation energy landscape shown in red. Note that the free energy per monomer of oligomeric and fibrillar states sampled during aggregation is concentration dependent and thus unrelated to the free energy of states sampled during unimolecular folding of protein monomers. Within the aggregation landscape, different possible conformations of dimeric and elongated/pore-forming hexameric species are sketched, representative of the polymorphism of oligomers populated during aggregation. The polymorphism of fibrillar states is highlighted by displaying the different structures of amyloid fibrils of Aβ1-40 (Meinhardt et al., 2009) and insulin (Jiménez et al., 2002). The possibility of amyloid formation via a run-away domain swap mechanism is also shown.
Molecular Cell  , 8-18DOI: ( /j.molcel )
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5. Figure 4 Diversity of Precursor States
The tertiary structure of various amyloid precursor states determined by X-ray crystallography and solution NMR are shown in rainbow colors and cartoon representation. The center (purple area) shows 12 different fibrillar polymorphs of Aβ1-40 determined using cryo-EM (taken from Meinhardt et al., 2009) to emphasize the array of amyloid structures available to a protein sequence. The green and yellow areas display structural possibilities of monomers and oligomers that a particular polypeptide chain may explore en route to the final amyloid fold. Thus, the colored areas represent an ensemble of structures available to a polypeptide chain, the precise details of which are dependent on the amino acid sequence and solution conditions applied. A quantitative description of precisely how each individual conformer within each ensemble is interconnected during a pathway of assembly is an important unresolved question that will require future experimental and theoretical developments to solve.
Molecular Cell  , 8-18DOI: ( /j.molcel )
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6. Figure 5 Prion Conversion, Transmissibility, and Infectivity
The schematic shows two possible mechanisms by which conformational conversion in prions might occur. The template assistance model is accomplished via bimolecular collision between native and nonnative prion conformers (in green and red, respectively), which transforms the former into an amyloidogenic state. The seeded polymerization model assumes a coupled equilibrium toward the amyloidogenic state due to the high affinity between nonnative prion conformers. Once the thermodynamically unfavorable nucleation process is overcome, stable prion aggregates are elongated by adding on nonnative prion conformers. This process is accelerated and transmitted to the daughter cells by fragmentation.
Molecular Cell  , 8-18DOI: ( /j.molcel )
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